Circulating tumor cells (CTCs) offer a non-invasive means to serially sample tumor cells from patients with solid malignancies. Most current CTC capture devices rely on immunoaffinity using antibodies directed against epithelial cell adhesion molecule (EpCAM). This particular capture epitope is attractive for its presence in a wide variety of epithelial cancers, but relative absence in normal blood cells. This provides a strategy to specifically capture tumor cells in the blood of patients. However, there are variations of EpCAM levels between tumors, so a multiple epitope strategy could be more inclusive. Furthermore, there is indication that EpCAM is lost during the process of epithelial to mesenchymal transition (EMT), which has been implicated in metastasis. Therefore, the identification of novel CTC capture epitopes to deal with tumor epitope heterogeneity as well as potential biologically important changes in tumor cell surface epitopes is important to capture the full spectrum of CTCs.